A hallmark event in Alzheimer's disease (AD) is the misfolding, aggregation and brain deposition of amyloid beta (Abeta) protein in amyloid plaques. Several strategies have been proposed for AD treatment based on inhibiting the amyloid pathway. For the last several years we have been developing short synthetic peptides capable to bind Abeta but unable to become part of a beta-sheet structure (beta-sheet breaker peptides) as novel amyloid inhibitors. We identified a 5-residue peptide (iAbetap) able to inhibit and disassemble amyloid fibrils in vitro, to prevent Abeta neurotoxicity in cell culture, and to arrest and dissolve amyloid plaques in several in vivo animal models. Treatment with iAbeta5p also inhibited neuronal death, brain inflammation and memory impairment in vivo. In addition, the compound showed low toxicity, low immunogenicity, high solubility and reasonably high brain uptake. Based on these results, iAbeta5p is currently under clinical evaluation in humans as a possible treatment for AD. In spite of the good activity in vivo, one of the major weaknesses of this compound is that its peptide nature makes it rapidly degradable and low permeable across biological barriers. The major aim of this project is to use the knowledge accumulated over several years regarding the structure-activity relationship of the lead peptides as well as the tridimensional structure of iAbeta5p to identify non-peptide compounds having a similar structure and activity, but better drug-like properties. The specific aims are the following: 1, to design, synthesize, test and identify in vitro active beta-sheet breaker peptidemimetics. To reach this aim we will follow two parallel approaches: highthroughput screening of existing compounds having the relevant pharmacophore groups and rational design and synthesis of novel chemical compounds that mimic the structure of the lead beta-sheet breaker peptide; 2, characterization of newly identified small molecule beta-sheet breakers for pharmacological properties, including stability, bioavailability, brain uptake, selectivity and preliminary toxicology. 3, improve potency and drug-like properties of hit compounds by medicinal chemistry; 4, detailed study of the in vivo activity of selected compounds using transgenic mice models of AD. The findings obtained in this project should lead to the generation of second generation non-peptide beta-sheet breakers with improved drug-like properties, which will offer a great promise for the efficient treatment of AD. [unreadable] [unreadable] [unreadable]